Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide; CAP), a pungent principle of red pepper, having the formula ##STR1## has a variety of pharmacological actions on cardiovascular and respiratory system, and on nervous system. Topical application of CAP to the skin evoked pain and may be followed by a period of desensitization to noxious chemical, thermal and mechanical stimuli. However, the initial activation of C-fibre nociceptors to produce a burning pain sensation and the concomitant hypothermia limited its use, although some clinical trials in treatment of postherpetic neuralgia have been carried out recently.
A number of analogues of CAP including vanillylacylamides, homovanillyl acylamides, carbamate derivatives, sulfonamide derivatives, urea derivatives, aralkylamides and thioamides, aralkyl aralkanamides, phenylacetamides and phenylacetic acid esters have been synthesized, and some of them have also been evaluated for their pungent potencies, desensitizing effects and antinociceptive activities. However, as yet none have been found to surpass the effectiveness of CAP. The most potent of the analogues synthesized thus far is N-nonanoyl vanillylamide (nonivamide; NVA), found to have a pharmacological profile similar to that of CAP and has been used as a substitute for CAP in neurophysiological and neuropharmacological studies. It has the formula as follows and is available today both commercially and in reagent-grade purity. ##STR2## Besides, a novel analogue of CAP, olvanil (N-vanillyl-9-octadecenamide; NE-19550), has been claimed to be a new class of anti-inflammatory analgesic agent with high oral ED.sub.50 of 170 mg/kg.
Most of the analogues of CAP have been derived from modifications of either the acylamide linkage or the alkyl chain. Some observations have pointed to the central role of the phenolic hydroxyl group in the bioactivity of CAP.
Szolcsanyl and Jansco-Gabor in their articles, Arzneium.-Forsch./Drug Res. 25, 1877 (1975) and Arzneim.-Forsch./Drug Res. 26, 33 (1976), report that 3-methoxy, 4-hydroxy phenyl ring is essential to the pungency of the capsaicin molecule, wherein an ether linked analogues of CAP is synthesized by replacing the free phenolic OH group with OCH.sub.3 group. However, they also report that this replacement can lead to a marked decrease, or a complete loss of other bioactivities such as antinociceptive and hypothermic activities as well.
As a result of an extensive investigations to develop a more potent, less acute and cardiac toxicity agent than that of capsaicin or of its analogues, a novel series of ether linked analogues of N-nonanoyl vanillylamide have been newly synthesized in the present invention.
Accordingly, one object of the present invention is to provide new and useful ether linked analogues of N-nonanoyl vanillylamide and pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide a process for preparing the ether linked analogues of N-nonanoyl vanillylamide and pharmaceutically acceptable salts thereof.
A further object of the present invention is to provide a pharmaceutical composition containing, as an active ingredient, the ether linked analogues of N-nonanoyl vanillylamide or a pharmaceutically acceptable salt thereof.
Still another object of the present invention is to provide a method for the antinociceptive treatment comprising administrating to a mammal in need of said treatment an effective amount of the ether linked analogues of N-nonanoyl vanillylamide or a pharmaceutically acceptable salt thereof.